Medical treatment

ABSTRACT

A compound of formula I  
                 
 
     or a pharmaceutically acceptable salt thereof in which R 1  and R 2  are independently H or methyl (for example N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl amine hydrochloride optionally in the form of its monohydrate) is used for reducing insulin resistance in humans in whom Impaired Glucose Tolerance and Non-Insulin Dependent Diabetes Mellitus have not presented.

[0001] This invention relates to a method of reducing insulin resistancein humans in whom Impaired Glucose Tolerance (IGT) and Non-InsulinDependent Diabetes Mellitus (NIDDM) have not presented.

[0002] At present, a person who has a fasting plasma glucose level ofgreater then 7.8 mmol/l is classified as being diabetic (although thisvalue is currently under review and may soon be set at a lower level,between 6 and 7 mmol/l). However, there is a standard means ofclassifying whether or not a person is diabetic, and this is importantwhen a person has a fasting blood glucose level just below the abovestated level. This means is called the Oral Glucose Tolerance Test(OGTT).

[0003] The OGTT is conducted in the following manner. After an overnightfast of 10-16 hours, a fasting blood glucose reading is taken. Glucose(75 g) is administered orally in water (250-300 ml). A further bloodglucose reading is taken after 2 hours. Diabetes is diagnosed if thefasting glucose level is greater than 7.8 mmol/l or if the 2 hour levelis greater than 11.1 mmol/l. Impaired Glucose Tolerance (IGT) isdiagnosed if the fasting glucose level is less than 7.8 mmol/l and the 2hour value is in the range 7.81-11.1 mmol/l. Normal glucose tolerance isdeclared if both the fasting glucose level and the 2 hour level are lessthan 7.8 mmol/l.

[0004] The majority of people are non-diabetic and have normal glucosetolerance. A proportion of these people will be at risk of developingImpaired Glucose Tolerance and/or diabetes in the future. Onewell-documented risk-factor is obesity, in which mild insulin resistanceis a common phenomenon. This is often compensated for in the obese bodyby an increase in the plasma insulin level. However, the body can onlyincrease its insulin secretion to a certain level, so if the insulinresistance continues to worsen in an obese person, eventually the bodywill not be able to compensate by providing extra insulin. At this timethe plasma glucose levels will start to become elevated, presenting IGTor Non-Insulin Dependent Diabetes Mellitus (NIDDM).

[0005] Clearly, this gradual decline towards IGT and NIDDM isundesirable both for the individual and in terms of the cost ofhealthcare. It would, therefore, b advantageous to restrict insulinresistance for as long as possible in these people.

[0006] The term “glucose tolerance” includes glucose disposal in muscletissue, and hepatic glucose output.

[0007] The term “Insulin resistance” means a reduced biological responseto insulin. Insulin resistance can involve effects on both hepaticglucose output and peripheral glucose uptake, and may be due to reducedinsulin receptor numbers, reduced tyrosine kinase activity of theinsulin receptor and/or abnormalities distal to the receptor.

[0008] Surprisingly, it has now been found that the administration ofcertain arylcyclobutylalkylamines has efficacy in reducing insulinresistance.

[0009] According to the present invention there is provided a method forreducing insulin resistance in humans in whom Impaired Glucose Toleranceor Non-Insulin Dependent Diabetes Mellitus have not presented but inwhom there is an increased risk of developing such conditions, saidmethod comprising administering to a human in need thereof atherapeutically effective amount of a compound of formula I

[0010] including enantiomers and pharmaceutically acceptable saltsthereof, in which R₁ and R₂ are independently H or methyl, inconjunction with a pharmaceutically acceptable diluent or carrier. Thehuman may be obese or may be not obese.

[0011] The preparation and use of compounds of formula I, such asN,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine (orN-{1-[1-(4-chlorophenyl)-cyclobutyl]-3-methylbutyl}-N,N-dimethylamine)and salts thereof, in the treatment of depression is described inBritish Patent Specification 2098602. The use of compounds of formula Isuch as N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamineand salts thereof in the treatment of Parkinson's disease is describedin European Patent Number 282206. The use ofN,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine andsalts thereof in the treatment of cerebral function disorders isdescribed in U.S. Pat. No. 4,939,175. The use ofN,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylaminehydrochloride in the treatment of obesity is described in EuropeanPatent Number 397831. A particularly preferred form of this compound isN,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylaminehydrochloride monohydrate (sibutramine hydrochloride monohydrate) whichis described in European Patent Number 230742. The use ofN,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine andsalts thereof for improving the glucose tolerance of humans havingImpaired Glucose Tolerance or Non-Insulin Dependent Diabetes Mellitus isdescribed in published PCT application WO95/20949. It does not discloseor suggest that the compounds of the present invention possess aninsulin sensitising activity, nor does it disclose or suggest that thecompounds of the present invention would be able to reduce insulinresistance in humans in whom IGT and NIDDM have not presented.

[0012] It may be appreciated by those skilled in the art that compoundsof formula I may exist as salts with pharmaceutically acceptable acids.Examples of such salts include hydrochlorides, hydrobromides, sulphates,methanesulphonates, nitrates, maleates, acetates, citrates, fumarates,tartrates [eg (+)-tartrates, (−)-tartrates or mixtures thereof includingracemic mixtures], succinates, benzoates and salts with amino acids suchas glutamic acid. Compounds of formula I and their salts may exist inthe form of solvates (for example hydrates).

[0013] It will be appreciated by those skilled in the art that compoundsof formula I contain a chiral centre. When a compound of formula Icontains a single chiral centre it may exist in two enantiomeric forms.The present invention includes the use of the individual enantiomers andmixtures of the enantiomers. The enantomers may be resolved by methodsknown to those skilled in the art, for example by formation ofdiastereoisomeric salts or complexes which may be separated, forexample, by crystallisation; via formation of diastereoisomericderivatives which may be separated, for example, by crystallisation,gas-liquid or liquid chromatography; selective reaction of oneenantiomer with an enantiomer-specific reagent, for example enzymaticoxidation or reduction, followed by separation of the modified andunmodified enantiomers; or gas-liquid or liquid chromatography in achiral environment, for example on a chiral support, for example silicawith a bound chiral ligand or in the presence of a chiral solvent. Itwill be appreciated that where the desired enantiomer is converted intoanother chemical entity by one of the separation procedures describedabove, a further step is required to liberate the desired enantiomericform. Alternatively, specific enantiomers may be synthesised byasymmetric synthesis using optically active reagents, substrates,catalysts or solvents, or by converting one enantiomer to the other byasymmetric transformation.

[0014] Specific compounds of formula I areN,N-dimethyl-1-[1-(4-chlorophenyl)-cyclobutyl]-3-methylbutylamine,N-{1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl}-N-methylamine, and1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine including racemates,individual enantiomers and mixtures thereof, and pharmaceuticallyacceptable salts thereof. A preferred compound of formula I isN,N-dimethyl-1-[1-(4-chlorophenyl)-cyclobutyl]-3-methylbutylamine or asalt thereof, for example the hydrochloride salt. A preferred form ofthis hydrochloride is its monohydrate.

[0015] The compound of formula I may be administered in any of the knownpharmaceutical dosage forms. The amount of the compound to beadministered will depend on a number of factors including the age of thepatient, the severity of the condition and the past medical history ofthe patient and always lies within the sound discretion of theadministering physician but it is generally envisaged that the dosage ofthe compound to be administered will be in the range 0.1 to 50 mgpreferably 1 to 30 mg per day given in one or more doses.

[0016] Oral dosage forms are the preferred compositions for use in thepresent invention and these are the known pharmaceutical forms for suchadministration, for example tablets, capsules, granules, syrups andaqueous or oil suspensions. The excipients used in the preparation ofthese compositions are the excipients known in the pharmacist's artTablets may be prepared from a mixture of the active compound withfillers, for example calcium phosphate; disintegrating agents, forexample maize starch; lubricating agents, for example magnesiumstearate; binders, for example microcrystalline cellulose orpolyvinylpyrrolidone and other optional ingredients known in the art topermit tableting the mixture by known methods. The tablets may, ifdesired, be coated using known methods and excipients which may includeenteric coating using for example hydroxypropylmethylcellulosephthalate. The tablets may be formulated in a manner known to thoseskilled in the art so as to give a sustained release of the compounds ofthe present invention. Such tablets may, if desired, b provided withenteric coatings by known methods, for example by the use of celluloseacetat phthalat. Similarly, capsules, for example hard or soft gelatincapsules, containing the active compound with or without addedexcipients, may be prepared by known methods and, if desired, providedwith enteric coatings in a known manner. The contents of the capsule maybe formulated using known methods so as to give sustained release of theactive compound. The tablets and capsules may conveniently each contain1 to 50 mg of the active compound.

[0017] Other dosage forms for oral administration include, for example,aqueous suspensions containing the active compound in an aqueous mediumin the presence of a non-toxic suspending agent such as sodiumcarboxy-methylcellulose, and oily suspensions containing a compound ofthe present invention in a suitable vegetable oil, for example arachisoil. The active compound may be formulated into granules with or withoutadditional excipients. The granules may be ingested directly by thepatient or they may be added to a suitable liquid carrier (for example,water) before ingestion. The granules may contain disintegrants, eg aneffervescent couple formed from an acid and a carbonate or bicarbonatesalt to facilitate dispersion in the liquid medium.

[0018] The therapeutically active compounds of formula I may beformulated into a composition which the patient retains in his mouth sothat the active compound is administered through the mucosa of themouth.

[0019] Dosage forms suitable for rectal administration are the knownpharmaceutical forms for such administration, for example, suppositorieswith cocoa butter or polyethylene glycol bases.

[0020] Dosage forms suitable for parenteral administration are the knownpharmaceutical forms for such administration, for example sterilesuspensions or sterile solutions in a suitable solvent.

[0021] Dosage forms for topical administration may comprise a matrix inwhich the pharmacologically active compounds of the present inventionare dispersed so that the compounds are held in contact with the skin inorder to administer the compounds transdermally. A suitable transdermalcomposition may be prepared by mixing the pharmaceutically activecompound with a topical vehicle, such as a mineral oil, petrolatumand/or a wax, e.g. paraffin wax or beeswax, together with a potentialtransdermal accelerant such as dimethyl sulphoxide or propylene glycol.Alternatively the active compounds may be dispersed in apharmaceutically acceptable cream, gel or ointment base. The amount ofactive compound contained in a topical formulation should be such that atherapeutically effective amount of the compound is delivered during theperiod of time for which the topical formulation is intended to be onthe skin.

[0022] The therapeutically active compound of formula I may beformulated into a composition which is dispersed as an aerosol into thepatients oral or nasal cavity. Such aerosols may be administered from apump pack or from a pressurised pack containing a volatile propellant.

[0023] The therapeutically active compounds of formula I used in themethod of the present invention may also be administered by continuousinfusion either from an external source, for example by intravenousinfusion or from a source of the compound placed within the body.Internal sources include implanted reservoirs containing the compound tobe infused which is continuously released for example by osmosis andimplants which may be (a) liquid such as an oily suspension of thecompound to be infused for example in the form of a very sparinglywater-soluble derivative such as a dodecanoate salt or a lipophilicester or (b) solid in the form of an implanted support, for example of asynthetic resin or waxy material, for the compound to be infused. Thesupport may be a single body containing all the compound or a series ofseveral bodies each containing part of the compound to be delivered. Theamount of active compound present in an internal source should be suchthat a therapeutically effective amount of the compound is deliveredover a long period of time.

[0024] In some formulations it may be beneficial to use the compounds ofthe present invention in the form of particles of very small size, forexample as obtained by fluid energy milling.

[0025] In the compositions of the present invention the active compoundmay, if desired, be associated with other compatible pharmacologicallyactive ingredients.

[0026] The following in vitro and in vivo tests support the finding thatcompounds of formula I have efficacy in reducing insulin resistance, andmay have an insulin sensitising action. It will be appreciated by thoseskilled in the art that 10 mg of sibutramine in the form of thehydrochloride monohydrate is equivalent to 8.37 mg of sibutramine asfree base.

Study 1 In vitro L6 Muscle Cells

[0027] L6 Muscle cells were obtained from the European CultureCollection (Porton Down) and were used at passages 7-11. Cells weremaintained in standard tissue culture medium DMEM, and glucose uptakewas assessed using [³H]-2-deoxyglucose (2DG) with and without thepresence of added insulin (10⁻⁸ M) as has been previously described(Walker P S et al, Glucose transport activity in L6 muscle cells isregulated by the coordinate control of subcellular glucose transporterdistribution, biosynthesis, and mRNA transcription, JBC,1990;265(3),1516-1523, and Kilp A et al, Stimulation of hexose transportby metformin in L6 muscle cells in culture, Endocrinology,1992;130(5),2535-2544).

[0028] Uptake of 2DG was expressed as the percentage change comparedwith control. Values are presented as mean ±SEM of sets of 4 wells perexperiment. Differences between sets of wells were evaluated byStudent's t test, probability values p<0.05 were considered to besignificant. In the absence of added insulin, L6 cells incubated for 24hours with the compound of formula I in which R₁ and R₂ are both H,showed a significant increase in 2DG uptake (from 100±2.1 in controls to116.9±3.8, 123.9±4.3 and 134±7.3 at 10⁻⁸, 10⁻⁷ and 10⁻⁶ M respectively).In the presence of added insulin (10⁻⁸ M), significant increases in 2DGuptake were observed following 24 hour incubation with the compound offormula I in which R₁ and R₂ are both methyl (sibutramine hydrochloridemonohydrate) at 10⁻⁸ M (from 149.9±4.3 to165.3±2.6), the compound offormula I in which R₁ is methyl and R₂ is H at 10⁻⁷ M (from 147.3±3.0 to160.7±4.5), and the compound of formula I in which R₁ and R₂ are both H,at 10⁻⁷ M and 10⁻⁶ M (from 149.1±3.9 to 161.8±3.3 and 165.2±3.6respectively).

[0029] This study shows that in the presence or absence of addedinsulin, compounds of formula I increase glucose uptake in L6 musclecells.

Study 2—In vivo ob/ob Mice

[0030] Studies were performed in obese ob/ob mice (Aston Strain) whichare a model of severe insulin resistance and are also hyperglycaemic.The derivation and characteristics of this animal model have beenpreviously described (Flatt P R, Bailey C J, Development of glucoseintolerance and impaired plasma insulin response to glucose in obesehyperglycaemic (ob/ob) mice, Horm Metab Res 1981;13:556-560, and BaileyC J et al, Influence of genetic background and age on the expression ofthe obese hyperglycaemic syndrome in Aston ob/ob mice, Int J Obesity,1982;6:11-21).

[0031] The ob/ob mice were individually housed in polypropylene cages ata temperature of 21±1° C. and 55% humidity. The mice had free access toa standard rat and mouse pelleted diet (Compound Rat and Mouse Diet,Special Diet Services, Witham, Essex) and tap water at all times.Animals were maintained on a reverse phase light-dark cycle. Lights wereoff between 09.00 h and 17.00 h in the acute experiment and between10.00 h and 18.00 h in the chronic experiment. During this time thelaboratory was illuminated by red lamps. Animals were acclimatised tothese conditions for at least two weeks before experimentation.

[0032] All animals were given deionised water (at the start of the darkperiod) for 7 days. Body weight and food intake were measured daily.Blood samples were taken immediately before daily administration ofvehicle (deionised water 10 ml/kg po) or compound of formula I in whichR₁ and R₂ are both methyl (sibutramine hydrochloride monohydrate; 10mg/kg po) on day 1 (baseline) and after 14 and 28 days of treatment (onday 15 and day 29 respectively). Blood samples were also taken 14 daysfollowing withdrawal of the sibutramine hydrochloride monohydrate (onday 43 of the study). Plasma glucose was determined by a glucose oxidaseprocedure (Analox GM7) and plasma insulin determined by radioimmunoassay(Amerlex, Amersham).

[0033] No significant changes in body weight or food intake wereobserved between vehicle and sibutramine hydrochloride monohydrate.Plasma glucose in sibutramine hydrochloride monohydrate-treated ob/obfell after 14 and 28 days of treatment, with a significant differencefrom control at day 28 (P<0.01, Table 1). After 14 days of drugwithdrawal, plasma glucose was unaffected in the vehicle dosed group butrose significantly in the sibutramine hydrochloride monohydrate treatedgroup to control values. No significant changes in plasma insulin wereobserved though plasma insulin tended to fall in the sibutraminehydrochloride monohydrate treated group and increased on compoundwithdrawal.

Study 3—In vivo ob/ob Mice

[0034] Young ob/ob mice (Aston Strain) were randomised into 3 groups asfollows: control, receiving placebo treatment (phosphate buffered saline2.5 ml/kg/day po); sibutramine hydrochloride monohydrate-treated (5mg/kg/day po); and pair-fed control, supplied with the same daily foodintake as that consumed by the sibutramine hydrochloridemonohydrate-treated group on the previous day. There was a 1 week run-inperiod followed by 6 weeks of treatment. Body weight and food intakewere monitored every 1 to 2 days, and blood samples for plasma glucoseand insulin were taken from the tail vein at weekly intervals in thenon-fasted state at 11 a.m. An ip glucose tolerance test (D-glucose, 2g/kg in 40% w/v solution in distilled water) and an insulinhypoglycaemia test (Actrapid, Novo-Nordisk, 2.5 u/kg ip) were conductedafter 5 weeks of treatment. Food was withheld only for the duration ofthese tests (approx. 4 hours). The basal blood samples and the testprocedures were undertaken 18 hours after the last treatmentadministration.

[0035] Treatment was stopped after 6 weeks, and the mice were monitoredfor the next 6 weeks. The pair-fed mice continued to be pair-fed withrespect to the sibutramine hydrochloride monohydrate withdrawal group. Asecond insulin hypoglycaemia test was conducted 4 weeks after treatmentwas stopped. Plasma glucose was determined by an automated glucoseoxidase procedure (Beckman) and plasma insulin determined byradioimmunnoassay (Amerlex, Amersham).

[0036] During sibutramine hydrochloride monohydrate treatment,significant reduction in body weight and plasma insulin compared tovehicle were observed. In an ip glucose tolerance test significantreductions in plasma insulin (P<0.05; see FIG. 1) and in plasma glucose(P<0.05; see FIG. 2) were observed with sibutramine hydrochloridemonohydrate treatment compared to the vehicle treated group. Significantimprovements in insulin hypoglycaemia (P<0.05; see FIG. 3; at 5 weeks)with sibutramine hydrochloride monohydrate treatment compared to thevehicle treated group were also observed. These results indicate thatcompounds of formula I, at a relatively low dose, are able to provide animprovement in insulin sensitivity because there is better glucoseutilisation with less insulin. The pair-fed group showed a similarweight reduction to the sibutramine hydrochloride monohydrate treatedgroup, but no improvement was observed in the oral glucose tolerancetest. Therefore the pair-fed group do not show an improvement in insulinsensitivity.

[0037] During the sibutramine hydrochloride monohydrate withdrawalperiod, body weight and plasma insulin remained significantly lower thanthe vehicle treated group for almost all of the 6 week withdrawalperiod.

[0038] In Table 1 and FIGS. 1-3, “sibutramine” indicates “sibutraminehydrochloride monohydrate”. TABLE 1 Effect of chronic administration ofthe compound of formula I in which R₁ and R₂ are both methyl (10 mg/kapo) and its withdrawal on plasma glucose and plasma insulin in ob/obmice. Day of Treatment Vehicle Compound Plasma glucose (mmol/l) Plasmainsulin (ng/ml) Treatment. Study Days (n) (n) Vehicle Compound VehicleCompound Prior to 1 0 22 32 24.3 ± 0.6 24.3 ± 0.6  92.0 ± 4.5 92.0 ±4.5  treatment Sibutramine 15 14 22 32 21.7 ± 0.9 19.0 ± 0.6  49.7 ± 3.545.1 ± 2.6  Sibutramine 29 28 14 21 26.0 ± 1.4 15.8 ± 0.7** 46.2 ± 4.535.1 ± 2.7  Drug 43 14 6 12 22.9 ± 1.7 23.6 ± 1.2  40.6 ± 8.6 77.1 ±11.3 Withdrawal

[0039] The data from the three studies indicate that compounds offormula I can enhance both basal and insulin stimulated glucose uptakeinto the L6 muscle cells and that in the absence of changes in eitherbody weight or food intake, the compound of formula I in which R₁ and R₂are both methyl can reduce plasma glucose levels in ob/ob mice. Thesedata taken together suggest an insulin sensitising action of compoundsof formula I. The data also indicate the ability of compounds of formulaI to decrease insulin resistance.

[0040] There are a several syndromes, such as acanthosis nigricans,leprechaunism, lipoatrophy and polycystic ovary syndrome, which exhibitinsulin resistance as part of their profile. The above data suggest thata compound of formula I may have utility in alleviating the insulinresistance in humans having such conditions. Therefore the presentinvention further provides the use of a compound of formula I in themanufacture of a medicament for reducing insulin resistance in humanshaving acanthosis nigricans, leprechaunism, lipoatrophy or polycysticovary syndrome or other conditions in which insulin resistance ispresent.

[0041] The present invention also provides a method of treatment foracanthosis nigricans, leprechaunism, lipoatrophy or polycystic ovarysyndrome or other conditions in which insulin resistance is present,comprising administration of a compound of formula I to a patient inneed thereof in conjunction with a pharmaceutically acceptable diluentor carrier.

[0042] NIDDM patients are often treated with oral insulin secretagogues,such as 1,1-dimethyl-2-(2-morpholinophenyl)guanidine fumarate (BTS67582)or sulfonylureas including tolbutamide, tolazamide, chlorpropamide,glibenclamide, glimepiride, glipizide and gliclazide, or with insulinsensitising agents including metformin, ciglitazone, troglitazone andpioglitazone. A further use of a compound of formula I is in themanufacture of a medicament, for combination therapy of NIDDM patientsto improve their weight and diabetic control, comprising a compound offormula I and an oral insulin secretagogue or an insulin sensitisingagent.

[0043] The present invention further provides a method of improving theweight and diabetic control of NIDDM patients comprising theadministration of a compound of formula I in combination with an oralinsulin secretagogue or an insulin sensitising agent in conjunction witha pharmaceutically acceptable diluent or carrier to a human in needthereof.

[0044] Preferably, the oral insulin secretagogue is1,1-dimethyl-2-(2-morpholino phenyl)guanidine fumarate (BTS67582) or asulphonylurea selected from tolbutamide, tolazamide, chlorpropamide,glibenclamide, glimepiride, glipizide and gliclazide. Preferably, theinsulin sensitising agent is selected from metformin, ciglitazone,troglitazone and pioglitazone.

[0045] The compound of formula I and the oral insulin secretagogue orinsulin sensitising agent may be administered either concomitantly orconcurrently, for example in the form of separate dosage units to beused simultaneously, separately or sequentially. Accordingly, thepresent invention further provides a product containing a compound offormula I and an oral insulin secretagogue or insulin sensitising agentas a combined preparation for simultaneous, separate or sequential usefor the improvement of weight and diabetic control in NIDDM patients.The ratio of the compound of formula I to the oral insulin secretagogueor insulin sensitising agent is such that the quantity of each activeingredient employed will be such as to provide a therapeuticallyeffective level, but will not be larger than the quantity recommended assafe for administration.

[0046] The action of reducing insulin resistance shown by compounds offormula I indicates that compounds of formula I may be useful in themanufacture of a medicament which can be used as an insulin sensitiser.Accordingly, the present invention further provides the use of acompound of formula I in the manufacture of a medicament which is aninsulin sensitiser.

[0047] Some patients who are diagnosed as being Insulin DependentDiabetics can also show a certain amount of insulin resistance.Therefore, there may be benefits in treating these patients with acompound of formula I in order to reduce their insulin resistance. Thiswould mean that these patients would require a lower dosage of insulinin order to maintain similar or better control of their diabetes sincethe insulin dose would be associated with a greater blood glucoselowering efficacy. Such therapy would provide long-term benefits interms of reducing the detrimental effects which can be caused byprolonged high-dosage of insulin treatment Additionally, some NIDDMpatients are also treated with insulin and have insulin resistance.Accordingly the present invention further provides a method for, and theuse of a compound of formula I in the manufacture of the medicament for,reducing the amount of insulin required daily by a human having InsulinDependent Diabetes Mellitus or NIDDM. The present invention alsoprovides a method for, and the use of a compound of formula I in themanufacture of a medicament for, the prophylaxis of long-termdetrimental effects caused by prolonged high dosage of insulin in humanshaving Insulin Dependent Diabetes Mellitus or NIDDM.

1. A method of reducing insulin resistance in humans in whom ImpairedGlucose Tolerance or Non-Insulin Dependent Diabetes Mellitus have notpresented but in whom there is an increased risk of developing suchconditions, said method comprising administering to a human in needthereof a therapeutically effective amount of a compound of formula I

including enantiomers and pharmaceutically acceptable salts thereof inwhich R₁ and R₂ are independently H or methyl, in conjunction with apharmaceutically acceptable diluent or carrier.
 2. A method as claimedin claim 1 in which the human is not obese.
 3. A method as claimed inclaim 1 in which the human is obese.
 4. A method as claimed in anypreceding claim wherein the compound of formula I isN,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylaminehydrochloride.
 5. A method as claimed in any preceding claim wherein thecompound of formula I isN,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylaminehydrochloride in the form of its monohydrate.
 6. Use of a compound offormula I

including enantiomers and pharmaceutically acceptable salts thereof inwhich R₁ and R₂ are independently H or methyl, in the manufacture of amedicament for reducing insulin resistance in humans in whom ImpairedGlucose Tolerance and Non-Insulin Dependent Diabetes Mellitus have notpresented but in whom there is an increased risk of developing suchconditions.
 7. The use as claimed in claim 6 in which the human is notobese.
 8. The use as claimed in claim 6 in which the human is obese. 9.The use as claimed in claim 6, 7 or 8 in which the compound of formula Iis N,N-dimethyl-1-[1-(4-chorophenyl)cyclobutyl]-3-methylbutylaminehydrochloride.
 10. The use as claimed in claim 6, 7 or 8 in which thecompound of formula I isN,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylaminehydrochloride mono-hydrate.
 11. A pharmaceutical composition forreducing insulin resistance in humans in whom Impaired Glucose Toleranceand Non-Insulin Dependent Diabetes Mellitus have not presented but inwhom there is an increased risk of developing such conditions,comprising a therapeutically effective amount of a compound of formula I

including enantiomers and pharmaceutically acceptable salts thereof inwhich R₁ and R₂ are independently H or methyl, in conjunction with apharmaceutically acceptable diluent or carrier.
 12. A pharmaceuticalcomposition as claimed in claim 11 in which the compound of formula I isN,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylaminehydrochloride.
 13. A pharmaceutical composition as claimed in claim 11in which the compound of formula I isN,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylaminehydrochlorid monohydrate.
 14. Use of a compound of formula I in themanufacture of a medicament which is an insulin sensitiser.
 15. Use of acompound of formula I in the manufacture of a medicament for reducingthe amount of insulin required daily by a human having Insulin DependentDiabetes Mellitus or NIDDM.
 16. Use of a compound of formula I in themanufacture of a medicament for the prophylaxis of long-term detrimentaleffects caused by prolonged high doses of insulin in humans havingInsulin Dependent Diabetes Mellitus or NIDDM.
 17. Use of a compound offormula I in the manufacture of a medicament for the prophylaxis ofImpaired Glucose Tolerance and Non-Insulin Dependent Diabetes Mellitusin humans having a high risk of developing the same.
 18. Use as claimedin claim 17 in which the human is not obese.
 19. Use of a compound forformula I in the manufacture of a medicament for reducing insulinresistance in humans having acanthosis nigricans, leprechaunism,lipoatrophy or polycystic ovary syndrome or other conditions in whichinsulin resistance is present.
 20. Use of a compound of formula I in themanufacture of a medicament for combination therapy of NIDDM patients toimprove their weight and diabetic control, comprising a compound offormula I and an oral insulin secretagogue or insulin sensitising agent.21. A method of improving the weight and diabetic control of NIDDMpatients comprising the administration of a compound of formula I incombination with an oral insulin secretagogue or insulin sensitisingagent in conjunction with a pharmaceutically acceptable diluent orcarrier to a human in need thereof.
 22. A product containing a compoundof formula I and an oral insulin secretagogue or insulin sensitisingagent as a combined preparation for simultaneous, separate or sequentialuse for the improvement of weight and diabetic control in NIDDMpatients.
 23. A product comprising a pharmaceutical composition whichcomprises a compound of formula I and an oral insulin secretagogue orinsulin sensitising agent together with a pharmaceutically acceptablediluent or carrier.
 24. A product as claimed in claim 22 or 23 in whichthe oral insulin secretagogue is1,1-dimethyl-2-(2-morpholinophenyl)guanidine fumarate (BTS67582) or asulfonylurea selected from tolbutamide, tolazamide, chlorpropamide,glibenclamide, glimepiride, glipizide and gliclazide.
 25. A product asclaimed in claim 22 or 23 in which the insulin sensitising agent isselected from metformin, ciglitazone, troglitazone and pioglitazone. 26.A method for reducing the amount of insulin required daily by a humanhaving Insulin Dependent Diabetes Mellitus or NIDDM comprising theadministration of a compound of formula I in conjunction with apharmaceutically acceptable diluent or carrier to a human in needthereof.
 27. A method for the prophylaxis of long-term detrimentaleffects caused by prolonged high doses of insulin in humans havingInsulin Dependent Diabetes Mellitus or NIDDM comprising theadministration of a compound of formula I in conjunction with apharmaceutically acceptable diluent or carrier to a human in needthereof.
 28. A method for the prophylaxis of Impaired Glucose Toleranceand Non-Insulin Dependent Diabetes Mellitus in humans having a high riskof developing the same comprising the administration of a compound offormula I in conjunction with a pharmaceutically acceptable diluent orcarrier to a human in need thereof.
 29. A method as claimed in claim 27in which the human is not obese.
 30. A method of reducing insulinresistance in humans having acanthosis nigricans, leprechaunism,lipoatrophy or polycystic ovary syndrome or other conditions in whichinsulin resistance is present comprising the administration of acompound of formula I in conjunction with a pharmaceutically acceptablediluent or carrier to a human in need thereof.